ALLEVIATION OF MONOCROTALINE-INDUCED PULMONARY-HYPERTENSION BY ANTIBODIES TO MONOCYTE CHEMOTACTIC AND ACTIVATING FACTOR MONOCYTE CHEMOATTRACTANT PROTEIN-1

Administration of monocrotaline (MCT) causes pulmonary vascular lesion s consisting of monocyte/macrophage infiltration in the early phase an d medial thickening in pulmonary arteries and arterioles associated wi th pulmonary hypertension (PH) in the later phase. However, the molecu lar mechanism of monocyte/macrophage infiltration and its roles remain elusive. Herein, we have evaluated the role of a potent monocyte chem otactic and activating chemokine/monocyte chemoattractant protein-1 (M CAF/MCP-1) in MCT-induced PH in rats. A single injection of MCT induce d PH at Day 21, as evidenced by increases in the ratio of right ventri cular to left ventricular and septum weights (RV/LV+S) and right ventr icular systolic pressure (RVSP). A significant increase in macrophage number in lungs started at Day 14, reaching a maximum at Day 21. MCAF/ MCP-1 levels in bronchoalveolar lavage fluids were elevated significan tly at Day 14 and remained high until Day 28, whereas plasma MCAF/MCP- 1 levels increased at Day 7, returning to normal levels by Day 21. Imm unoreactive MCAF/MCP-1 proteins were mainly detected in macrophages in alveoli and in perivascular regions of pulmonary arterioles and venul es. Intravenous administration of anti-MCAF/MCP-1 antibodies with MCT significantly decreased macrophage infiltration and eventually reduced the increases in RV/LV+S and RVSP, as well as medial thickening of pu lmonary arterioles. Thus, MCAF/MCP-1 is essentially involved in MCT-in duced PH by recruiting and activating macrophages.